This proposed project focuses on the structure-function relationship study and development of novel D-peptide ligands of chemokine receptor CXCR4 that inhibit the entry and infection of human immunodeficiency virus type 1 (HIV-1) via the CXCR4 coreceptor. Recently, chemokine receptors, mainly CXCR4 and CCR5 were discovered to be the coreceptors for HIV-1. Together with the primary receptor CD4, these chemokine coreceptors play an important role in HIV-1 pathogenesis. The ligands of these chemokine receptors, such as SDF-1? and vMIP-II that bind CXCR4 were shown to inhibit HIV-1 infection. In the past grant period, we have discovered DV1, a novel D-peptide derived from the N-terminus of vMIP- II that strongly inhibits CXCR4 function and HIV-1 entry and infection via this coreceptor. DV1 peptide is a highly potent CXCR4 inhibitor (receptor binding potency in the -13-32 nM concentrations) and shows high selectivity (at least >3,000 folds) against another chemokine receptor CCR5. Together with our collaborator Dr Joseph Sodroski at the Dana-Farber Cancer Institute of Harvard Medical School, we have demonstrated the selective anti-HIV activity of DV1 for CXCR4-dependent HIV-1 replication. Most recently, preliminary NMR studies of DV1 and its shorter analog DV3 have been conducted, which demonstrate the feasibility and importance of determining the high resolution structure of the inhibitors to provide a solid foundation for further structure-based drug design. Here in this renewal application we plan to extend these studies to further characterize the structure-function relationships of this DV1 inhibitor and develop more potent new analogs. In addition, we use these novel molecules as model systems to develop a general understanding of the interactions of chemokine receptors with their ligands.